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Mobile phone technology for reduced drinking : novel methods for measuring alcohol consumption and treating alcohol dependence
No full textBackground: Studies on the use of smartphone applications (apps) to curb alcohol consumption are limited but increasing. Previous studies show promising effects, especially on samples in the general population. The aim of this thesis was to enhance the understanding of using apps within addiction treatment. The research questions ranged from estimating the effectiveness (Study I) and examining the perceptions of the users (Studies II and IV), to testing the agreement between app reports and traditional methods for measuring alcohol consumption (Study III), and assessing factors needed for successful implementation (Study IV).Methods: The project was based on a randomised controlled trial (RCT). Alcohol-dependent patients with recent patterns of heavy drinking, no co- occurring drug dependence and limited psychosocial problems were recruited at an alcohol addiction clinic or by social media advertisements and were randomised to either treatment as usual (TAU) or TAU complemented with a drink-counting or breathalyser-coupled app for 12 weeks (Study I). TAU comprised four therapy sessions for 12 weeks, that could also be complemented with pharmacotherapy. Effects were measured at 12 weeks (post-intervention) and 26 weeks after randomisation (follow-up). The primary outcome was heavy drinking days in the past month at 26 weeks. A purposive sample of 21 participants that had used the apps later partook in individual interviews on their experiences (Study II). The apps were further tested in a subsequent study where app-based data (e.g., number of drinks, drinking days and heavy drinking days) were compared with traditional methods for assessing consumption (e.g., Timeline FollowBack) (Study III). Since the two apps were linked to online portals that shared data with clinic staff, focus group discussions were undertaken to explore clinicians' views on incorporating the apps into their treatment delivery (Study IV).Results: Results from Study I showed that the breathalyser-coupled app given as a complement to TAU was more effective than TAU alone in reducing heavy drinking days at 26 weeks (30-33 % lower rate). In Study II, results showed that the apps were considered relevant and helpful adjuncts to TAU by the patients. Nonetheless, app usage was hindered by primarily technical problems but also non-personalised procedures and features and usage among other people. Similarly, in Study IV, the clinicians believed that the apps offered several advantages for their patients, and that the portals could provide valuable support during treatment sessions. However, the breathalyser was considered unreliable, which further was believed to affect both their own, and their patients', motivation for sustained use. In Study III, it was found that the data from the drink-counting app, but not the breathalyser, well agreed with consumption reported in TLFB and PEth. For the successful implementation of the apps, Study IV found that ensuring their technical stability, protecting data security, and identifying patients at risk of adverse events were considered crucial. Additionally, several other factors, including education, support, additional time, and continuity, were deemed essential.Conclusion: Taken together, the results of this thesis show that a breathalyser- coupled smartphone application may be effective in reducing heavy drinking, and that a drink-counting app may be a useful and available tool for reporting alcohol consumption. Both apps have relevant features considered useful in treatment and provide an opportunity to enhance patient accountability in the change process. A person-centred approach is essential when using the smartphone-based interventions within addiction treatment, along with ensuring the necessary conditions (e.g., guidance, support, workflow and time management) for clinicians to effectively utilise the tools. Technical issues with the apps are a main barrier to their reliability and use and must be resolved before they can be integrated into routine care.List of scientific papersI. Östh, J., Lundin, A., Wennberg, P., Andréasson, S., & Danielsson, A. K. (2025). The effectiveness of a drink-counting and a breathalyser- coupled smartphone application for reduced heavy drinking among alcohol-dependent adults in Sweden: a randomised controlled trial. Addiction.https://doi.org/10.1111/add.16769II. Östh, J., Danielsson, A. K., Lundin, A., Wennberg, P., Andréasson, S., & Jirwe, M. (2024). Keeping Track of My Drinking - Patient Perceptions of Using Smartphone Applications as a Treatment Complement for Alcohol Dependence. Substance Use & Misuse, 59(2), 291-299.https://doi.org/10.1080/10826084.2023.2269578III. Östh, J., Lundin, A., Wennberg, P., Andréasson, S., & Danielsson, A. K. Measuring alcohol use: Comparing instant smartphone application- based reports with Timeline Followback, Alcohol Use Disorders Identification Test Consumption, and Phosphatidylethanol. [Manuscript] https://doi.org/10.1016/j.abrep.2025.100643IV. Östh, J., Lundin, A., Wennberg, P., Andréasson, S., & Danielsson, A. K. Clinicians' Perspectives on Integrating Smartphone Application Data into Routine Alcohol Dependency Treatment: Factors Influencing Implementation. [Manuscript] https://doi.org/10.1186/s13722-025-00597-4</p
Novel therapeutic targets and treatment strategies in paediatric brain tumours
No full textThe primary goal of Study I was to understand the effects of lithium on the tumour cells in Group 3 medulloblastoma, and whether it extends its radioprotective properties we see in the context of neural progenitors onto the tumour cells. We found that not only did lithium not protect the tumour cells from radiation, but it also possesses anti-tumour properties shown both in vitro and in vivo.Study II focused on the identification of novel markers of tumour evolution in medulloblastoma. In this study, we performed single-cell RNA sequencing on 14 medulloblastoma (MB) patients, comprised of all 4 molecular subgroups, as well as 6 additional publicly available datasets. By using different computational tools, we found that MB tumour cells cluster according to their copy number variation (CNV) load, with RNA velocity showing that they follow a temporal trajectory from those with low CNV levels to those with high. We then used this information and designated the cluster with a low CNV load as "early" and the clusters with high CNV levels as "later" tumour cells, allowing us to perform a differential gene expression analysis, identifying earlier and later tumour markers. Finally, we used Numbat to differentiate between the early and the late clones in individual samples, which allowed us to identify SOX4 as the only common marker upregulated in the later clones in all Group 3 and Group 4 samples.The main focus of Study III was to understand the role of microglia in the radiation- induced neuroinflammation proposed to be an important contributor to the loss of cognitive function seen in brain tumour patients that have undergone radiotherapy. We found a delayed microglial response 2 weeks after irradiation exhibiting an interferon-related inflammatory signature, as well as two waves of neuronal asynchrony associated with inflammation and aberrant synaptic regulation, respectively.The goal of Study IV was to classify microglial cells using deep learning algorithms and to develop spatial statistics pipelines to understand interactions between classified cells. Additionally, it was important for this tool to be adjustable to any cell type and to be applicable to brightfield and fluorescent microscopy.List of scientific papersI. Lithium decreases tumour growth in Group 3 medulloblastoma. Yana Ruchiy, Daniela Nunes, Casandra Salinas, Shigeaki Kanatani, Miao Zhao, Gabriela Rosen, Fredrik J Swartling, Carlos FD Rodrigues, Lena-Maria Carlson*, Klas Blomgren *. [Manuscript]II. Genomic tumor evolution dictates human medulloblastoma progression. Yana Ruchiy#, Ioanna Tsea#, Efthalia Preka, Bronte Manouk Verhoeven, Thale Kristin Olsen, Shenglin Mei, Indranil Sinha, Klas Blomgren, Lena-Maria Carlson*, Cecilia Dyberg*, John Inge Johnsen*, Ninib Baryawno *. Neuro-Oncology Advances. Volume 6, Issue 1, January-December 2024. https://doi.org/10.1093/noajnl/vdae172III. Microglia adopt temporally specific states after irradiation, correlating with neuronal asynchrony. Alejandro Lastra Romero#, Efthalia Preka#, Giusy Pizzirusso, Luis Enrique Arroyo-García, Georgios Alkis Zisiadis, Nuria Oliva-Vilarnau, Yana Ruchiy, Thea Seitz, Kai Zhou, Arturo Gonzalez Isla, Lara Friess, Ying Sun, Maria Querol Canut, Alia Shamik, Yiran Xu, Changlian Zhu, Carlos F. D. Rodrigues, André Fisahn, Bertrand Joseph, Lena-Maria Carlson, Adamantia Fragkopoulou, Volker M Lauschke, Christer Betsholtz, Ahmed M Osman*, Klas Blomgren *. [Manuscript]IV. Unravelling microglial spatial organization in the developing human brain with DeepCellMap, a deep learning approach coupled with spatial statistics. Theo Perochon, Zeljka Krsnik, Marco Massimo, Yana Ruchiy, Alejandro Lastra Romero, Elyas Mohammadi, Xiaofei Li, Katherine R. Long, Laura Parkkinen, Klas Blomgren, Thibault Lagache*, David A. Menassa*, David Holcman *. Nature Communications. 16, 1577 (2025). https://doi.org/10.1038/s41467-025-56560-z# Shared first authorship; * Shared senior authorship</p
Premenstrual disorders : risk determinants and health consequences across the life course
No full textPremenstrual disorders (PMDs), encompassing premenstrual syndrome (PMS) and more severe premenstrual dysphoric disorder (PMDD), are defined as cyclic somatic and affective symptoms in the days before menstruation. Despite evidence supporting the role of inflammation in the development of PMDs, it remained unknown if childhood asthma and allergies, inflammatory diseases which have common etiologies with PMDs, were linked to PMD risk. In addition, the causality for known risk factors of PMDs remained unclear and the long-term health outcomes of PMDs were also understudied.Study I examined the association between childhood asthma, allergies, and risk of PMDs in adulthood. We performed a prospective cohort study in the US from 1996 to 2013 (n=6,524), and found asthma was positively associated with PMDs (RR=1.20 (1.07-1.34)). In addition, food allergy was statistically associated with PMDs (RR=1.28 (1.06-1.54)), while eczema and hay fever showed borderline associations. In addition, asthma and food allergy showed a stronger association with probable PMDD than with PMS.Study II assessed causality for eight known-risk factors of PMDs using Mendelian randomization (MR). When performing MR with summary-level data, genetic liability to smoking initiation (OR=1.25 (1.10-1.43), Padjusted=0.005), earlier menarche (OR=0.94 (0.89-0.98) per year, padjusted=0.012), and higher body mass index (BMI) (OR=1.19 (1.05-1.34) per kg/m2, padjusted=0.012) were associated with an increased risk of PMDs. No causal associations were indicated for anemia, childhood abuse, childhood asthma, diabetes and endometriosis. When replicating the results using individual-level data in a Swedish cohort, consistent effect directions were indicated for BMI (OR = 1.10 (0.88-1.38) per kg/m2) and earlier menarche (OR = 0.98 (0.83-1.15) per year), whereas an inverse association was suggested for smoking (OR=0.94 (0.77-1.16)).Study III prospectively examined the associations between PMDs, early menopause, and vasomotor symptoms (VMS) in US women (N=3,635). During follow-up from 1991 to 2017, we found that having a PMD was related to increased risk of early natural menopause (HR=2.67 (1.27-5.59)). Women with PMDs were also at an increased risk of moderate/severe VMS (OR=1.68 (1.32- 2.14)), but no association was found for mild VMS (OR=0.99 (0.76-1.28)).Study IV evaluated whether women with PMDs had an increased risk of cardiovascular diseases (CVDs). We followed over 3 million women of reproductive age in Sweden from 2001 to 2022. In addition to population cohort, we also designed a sibling cohort to account for shared familial factors. Compared to women without PMDs, those with clinician-diagnosed PMDs had an increased risk of any CVD in population (HR=1.11 (1.08-1.13)) and sibling analyses (HR=1.10 (1.06-1.15)). Furthermore, in both population and sibling cohorts, PMDs were related with increased risk of several subtypes of CVDs, including arrhythmia, cerebrovascular disease, ischemic stroke, ischemic heart disease, hypertensive diseases and essential hypertension.Collectively, this doctoral thesis investigated childhood and adulthood risk determinants of PMDs, as well as its long-term health outcomes through and beyond menopause. Our findings emphasized the importance of adopting a life course approach to advance the understanding of PMD etiology, inform prevention and intervention strategies, and guide long-term clinical management.List of scientific papersI. Yang Y, Gong T, Camargo CA, Valdimarsdóttir UA, Bertone-Johnson E#, Lu D#. Childhood asthma, allergies and risk of premenstrual disorders in young adulthood. Nat Mental Health. 2023;1(6):410-419. https://doi.org/10.1038/s44220-023-00066-4II. Yang Y, Tang B, Hysaj E, Xiang N, Qu S, Hägg S, Valdimarsdóttir UA, Bertone- Johnson E, Lu Y, Lu D. An atlas of causal risk factors for premenstrual disorders: a wide-angled Mendelian randomization study. [Submitted]III. Yang Y, Valdimarsdóttir U A, Manson JE, Sievert LL, Harlow BL, Eliassen AH, Bertone-Johnson ER#, Lu, D#. Premenstrual Disorders, Timing of Menopause, and Severity of Vasomotor Symptoms. JAMA Netw Open. 2023;6(9):e2334545. https://doi.org/10.1001/jamanetworkopen.2023.34545IV. Yang Y, Bränn E, Zhou J, Wei D, Bergstedt J, Fang F, Valdimarsdóttir UA, Bertone-Johnson E, Lu D. Premenstrual disorders and risk of cardiovascular diseases. Nat Cardiovasc Res. 2025;4(8):1001-1010. https://doi.org/10.1038/s44161-025-00684-4#Equal contribution.</p
The long-term impact of severe maternal morbidity
No full textBackgroundSevere maternal morbidity (SMM) refers to life-threatening conditions or interventions occurring during pregnancy, delivery, or postpartum, and is widely used in high-income settings as a marker of maternal care quality. Although there is little international consensus on which conditions define SMM, several reports indicate it is increasing. SMM however has been associated with several adverse long-term outcomes in the affected women including accelerated mortality rate, increased risk of psychiatric disorders, cardiovascular diseases, recurrence of SMM in subsequent deliveriesAimThe aim of this thesis was to establish a thorough and validated definition of SMM for surveillance in Sweden, to examine SMM trends and regional variations, and to assess its associations with long-term outcomes, including the probability of a subsequent birth, risks of adverse reproductive, pregnancy, and neonatal outcomes, and work-loss through sick leave and disability pension.MethodsWe linked multiple national registers in Sweden (and in Study III, BC) using personal identification numbers. SMM was identified in all studies using a standardized list (adapted for Sweden) based on diagnostic and procedure codes during pregnancy and up to 42 days postpartum. In Study I, we described temporal trends and regional differences using rate ratios (RRs) and 95% CIs. In Study II, women with a recorded first delivery were followed from 43 days postpartum until conception of the second pregnancy, death, emigration, or 31 December 2021; Cox regression estimated associations between SMM and time to subsequent birth, and sibling analyses assessed familial confounding. In Study III, among women with both their first and second deliveries recorded, generalized linear models generated adjusted risk ratios (aRRs) and 95% CIs for pregnancy and delivery complications, composite severe neonatal morbidity, and perinatal mortality in the second birth. In Study IV, women with a first-ever SMM diagnosis were matched to women without SMM. Outcomes were disability pension and sick leave within three years after conception, analyzed using Cox regression for disability pension and tobit regression for net sickness daysResultsIn Study I, the overall SMM rate was 270.2 (95% CI 268.1-272.4) per 10,000 deliveries. Rates rose from 1999 to 2006 and then declined. The most common SMM types were severe preeclampsia/eclampsia/HELLP, severe hemorrhage, sepsis, embolism, DIC, shock, and severe mental health disorders. Severe hemorrhage peaked at 169.3 per 10,000 in 2006 before falling to 111.2 in 2019. Rates of embolism, DIC, shock, acute renal failure, cardiac complications, sepsis, and assisted ventilation increased, while surgical complications, severe uterine rupture, and anesthesia complications declined. In Study II, women with SMM had a lower rate of subsequent birth than those without SMM (aHR 0.88, 95% CI 0.87-0.89). The reduction was most pronounced for severe uterine rupture, cardiac complications, cerebrovascular accidents, and severe mental health disorders. Sibling analyses indicated that these associations were not explained by familial confounding. In Study III, women with SMM in their first delivery had an elevated risk of composite perinatal death/severe neonatal morbidity in their second delivery compared with those without SMM. In Sweden, prior SMM was associated with a 1.59-fold higher risk of stillbirth, 1.65-fold higher risk of neonatal mortality, 1.95-fold higher risk of severe neonatal morbidity, and a 1.69-fold higher risk of infant mortality. SMM in the first delivery was also linked to a 4.77-fold higher risk of recurrent SMM, a 6.20-fold higher risk of preeclampsia, and roughly twofold increased risks of placental abruption, maternal infection, and both antepartum and postpartum hemorrhage in the second delivery. In BC, we found estimates pointing in the same direction, although not all reached statistical significance. In Study IV, women with SMM had 33.4 more sickness-absence days (95% CI 32.0-34.8) after conception than women without SMM. After adjustment, SMM was associated with a 66% higher rate of receiving disability pension (95% CI 1.53-1.80). The rates of receiving disability pension were highest in the first postpartum year and, although declining, remained elevated five years later. Cerebrovascular events, cardiac disease, acute renal failure, assisted ventilation, and severe mental health conditions showed the strongest associations with prolonged sick leave and long-term disability.ConclusionThe proposed Swedish SMM definition can be used for surveillance and future research. Regional and temporal variations in SMM offer important insights and help identify priority areas for improving maternal health. SMM in the first birth is associated with reduced likelihood of a subsequent birth, emphasizing the importance of counseling and improved antenatal care. SMM in the first delivery was associated with an increased risk of adverse pregnancy, delivery, and offspring outcomes in the subsequent delivery, highlighting the importance of clinical and reproductive counseling for affected women. SMM increased the risk of disability pension and longer sick leave, highlighting the need for targeted public health initiatives and social insurance support.List of scientific papersI. Tsamantioti E, Sandström A, Muraca GM, Joseph KS, Remaeus K, Razaz N. Severe maternal morbidity surveillance, temporal trends and regional variation: A population-based cohort study. BJOG. 2024 May;131(6):811-822. Epub 2023 Oct 5. https://doi.org/10.1111/1471-0528.17686II. Tsamantioti E, Sandström A, Lindblad Wollmann C, Snowden JM, Razaz N. Association of Severe Maternal Morbidity With Subsequent Birth. JAMA. 2025 Jan 14;333(2):133-142. https://doi.org/10.1001/jama.2024.20957III. Tsamantioti E, Joseph KS, Ananth C, Remaeus K, Sandström A, Razaz N. Severe maternal morbidity and risk of adverse pregnancy, delivery, and neonatal outcomes in the subsequent delivery. AJOG. https://doi.org/10.1016/j.ajog.2025.11.026 [Accepted]IV. Tsamantioti E, Söderlig J, Remaeus K, Sandström A, Razaz N. Sickness leave and disability pension in women with severe maternal morbidity during pregnancy. [Manuscript]</p
The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy
No full textMammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.</p
Intracranial infections related to external ventricular drains in neurocritical care patients : diagnosis and treatment implications
No full textThis thesis addresses the critical challenge of diagnosing and managing external ventricular drain-associated infections (EVDIs) in neurocritical care. The neurosurgical intensive care unit (NICU) frequently admits patients with severe brain injuries, often requiring neurosurgical interventions such as external ventricular drain (EVD) placement to manage increased intracranial pressure (ICP) caused by intracranial hemorrhage and intraventricular hemorrhage. Although EVDs are essential for cerebrospinal fluid (CSF) diversion and ICP monitoring, they carry substantial risks, notably bacterial infections, which pose diagnostic and therapeutic dilemmas due to ambiguous clinical signs and the limitations of current EVDI surveillance methods. The resulting overuse of broad-spectrum antibiotics exacerbates concerns about antimicrobial resistance and patient safety. The overarching aim of this thesis was to critically appraise existing EVDI surveillance practices and develop improved or adjunct diagnostic strategies and methods to potentially guide EVDI-targeted treatment.In Study I we investigated the assumption that blood is evenly distributed within the ventricular space, an assumption underpinning current cell count-based infection markers. Using paired CSF samples before and after patient repositioning in the ICU, significant bi-directional variability in cell counts, glucose, and lactate was observed, affecting the EVDI classification of 30% of all patients. These findings challenge the validity of cell count metrics in EVDI surveillance, introducing considerable uncertainty in their use to inform clinical decision-making.In Study II we retrospectively assessed the performance of routine EVDI surveillance diagnostics at Karolinska University Hospital over a 17-year period. Results demonstrated poor discriminatory power of current EVDI surveillance diagnostics between infection and aseptic inflammation, contributing to a seven-to-one ratio of suspected to verified infections. Moreover, 15% of all ICU antibiotic use could be attributed to EVDI-targeted therapy, despite EVDI patients only representing approximately 3% of the total ICU population at our institution. Overall our findings suggested a need for more specific and sensitive methods to guide EVDI-targeted therapy.In Study III we retrospectively evaluated the potential use of 16S-rRNA sequencing, a molecular diagnostic technique capable of detecting bacterial genetic material, compared to the current gold standard CSF cultures in EVDI diagnostics. The study demonstrated comparable sensitivity and specificity, albeit lower positive predictive value, with the potential to reduce broad-spectrum antibiotic usage by 43-71% if results are obtained within 24 hours. As such, representing a promising method for potentially guiding EVDI-targeted therapy and improving antimicrobial stewardship.In Study IV, a proof-of-concept study, we prospectively evaluated a novel diagnostic platform based on loop-mediated isothermal amplification (LAMP) technology. EVDI specific test kits, tailored to detect EVDI-relevant bacterial pathogens, were developed through the compilation of microbiological findings globally through an extensive literature review as well as through the compilation of microbiological findings at our institution over a 15-year period. Our findings in this study suggests that LAMP- based methods, while demonstrating a high rate of contaminations, can facilitate timely pathogen identification, enabling targeted therapy and reducing unnecessary antibiotic exposure in an ICU setting.Overall, this research underscores the limitations of current EVDI surveillance paradigms and highlights promising current and future rapid molecular diagnostic testing modalities as tools for more accurate, sensitive, and timely infection detection. Implementing such adjunct diagnostics can potentially reduce broad-spectrum antibiotic use, mitigate antimicrobial resistance, and improve clinical outcomes in neurocritical care patients. Future efforts should focus on further exploring and integrating these innovative strategies into routine practice and evaluating their impact in prospective clinical trials.List of scientific papersI. Cerebrospinal fluid cell count variability is a major confounding factor in external ventricular drain-associated infection surveillance diagnostics: a prospective observational study. Marcus Bådholm, Jonas Blixt, Martin Glimåker, Anders Ternhag, Jonas Hedlund, and David W. Nelson Critical Care 25, no. 291 (11 August 2021). https://doi.org/10.1186/s13054-021-03715-1II. Performance of routine surveillance diagnostics of external ventricular drain- associated infections in a critical care setting: a retrospective cohort study. Marcus Ståhlberg, Jonas Blixt, Christer Mehle, Viveca Hambäck Hellkvist, Christian G. Giske, Eddie Weitzberg, and David W. Nelson Infectious Diseases 25, no. 646 (02 May 2025). https://doi.org/10.1186/s12879-025-11006-1III. Next-generation 16S-rRNA sequencing for diagnosing external ventricular drain-related infections in a critical care setting: a multi-center cohort study with implications for antibiotic stewardship. Marcus Ståhlberg, Joel Rahme, John Karlsson Valik, Christer Mehle, Jonas Blixt, Eddie Weitzberg, Christian G. Giske, and David W. Nelson. [Manuscript]IV. Loop-mediated isothermal amplification as a novel approach for early identification of meningitis in patients with external ventricular drains in a critical care setting: a prospective clinical proof-of-concept study. Marcus Ståhlberg, John Karlsson Valik, Jonas Blixt, Stina Hardell, Anette Ebberyd, Viveca Hambäck Hellkvist, Eddie Weitzberg, Christian G. Giske, and David W. Nelson. [Manuscript]</p
Movement behaviours in Swedish 3-9-year-olds : prevalence, associations with health markers, and promotion of healthy behaviours
No full textBackgroundMovement behaviours are comprised of physical activity, sedentary behaviour, and sleep and are important for children's physical health. The World Health Organization (WHO) 24-hour movement guidelines integrate these behaviours into three recommendations, recognising their interdependence within the 24- hour day. However, research on the prevalence of Swedish children adhering to these guidelines is limited. Understanding how movement behaviours relate to health markers in children, and how these behaviours can be supported early on, is important for promoting long-term health. In Sweden, nearly all children attend preschool, making it a key arena for health promotion, but limited research has explored how preschools can support healthy movement behaviours.AimThe overall aim of this thesis was to investigate movement behaviours in Swedish children aged 3-9 years, in terms of adherence to movement guidelines and associations with health markers. Another aim was to explore preschool teachers' and principals' perspectives on promoting healthy lifestyle behaviours in the preschool setting, as well as their preferences for digital support.MethodsPaper I: A cross-sectional study in 631 children 3-6 years of age from the Swedish arm of the International Study of Movement Behaviours in the Early Years (SUNRISE). Waist-worn accelerometers were used to measure physical activity and sedentary behaviour, whereas sleep and screen time were assessed through questionnaires. The prevalence of children adhering to the WHO 24- hour movement guidelines together and separately were investigated. Also, associations between reallocating time to either vigorous physical activity (VPA), moderate-to-vigorous physical activity (MVPA), or sedentary behaviour, at the expense of the remaining movement behaviours, with measures of physical fitness, anthropometry, and blood pressure were analysed using compositional data analysis.Paper II: A cross-sectional study in 411 children from Studies of Prospective Health Determinants in Infancy and Childhood (SPINACH) aged 9 years, investigating associations between sleep patterns, based on sleep duration and bedtime, and cardiometabolic risk factors. Sleep duration and bedtime were assessed with wrist-worn accelerometers and cardiometabolic risk factors included blood lipids, glucose, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), a metabolic syndrome score, waist circumference, and blood pressure. Children were categorised into four groups depending on if they adhered to the sleep recommendation or not and if they had an early or late bedtime, based on the median bedtime of the population. Associations between sleep patterns and cardiometabolic risk factors were investigated using analysis of covariance.Paper III: A cross-sectional and longitudinal study in 411 children from SPINACH at 4 and 9 years of age. Movement behaviours were assessed with wrist-worn accelerometers and screen time with questionnaires. Cardiometabolic risk factors included the same measures as in Paper II. Longitudinal associations of increasing sedentary time (at the expense of the remaining movement behaviours) at 4 years of age with cardiometabolic risk factors at 9 years of age were examined, as well cross-sectional associations at 9 years of age, using compositional data analysis. Associations between adherence to the screen time recommendation and cardiometabolic risk factors were also examined.Paper IV: Semi-structured interviews were conducted in 15 preschool teachers and principals. Content analysis was employed to explore perceptions, needs, and prerequisites for promoting healthy lifestyle behaviours in the preschool setting, as well as preferences for potential digital support.ResultsPaper I: Most children met the WHO guidelines for physical activity (95%) and sleep (94%), while fewer met the screen time recommendation (44%). Only 40% adhered to all three guidelines. Increasing VPA or MVPA while evenly reducing the remaining behaviours were associated with a stronger handgrip (both PPaper II: Children adhering to the sleep recommendation combined with having early bedtimes had lower insulin resistance (0.30 versus 0.60, P=0.025), metabolic syndrome score (-0.15 versus 0.42, P=0.029), and insulin levels (6.80 versus 8.87 mIU/L, P=0.034), compared to the group who did not adhere and had late bedtimes. In the model where total sleep time was added as an additional covariate, a significant association was still observed with metabolic syndrome score (-0.19 versus 0.50, respectively, P=0.011).Paper III: Increased sedentary behaviour at the expense of the other movement behaviours at age 9 was associated with higher systolic (P=0.021) and diastolic (P=0.019) blood pressure. In the longitudinal analysis, reallocating time to sedentary behaviour while evenly reducing the remaining behaviours at age 4 was significantly associated with higher diastolic blood pressure (PPaper IV: Teachers and principals considered the preschool environment and themselves as essential in the promotion of healthy lifestyle behaviours in the preschool setting. They highlighted collaboration with parents, a need for clear guidance in policies and curriculum as well as face-to-face support, such as workshops and lectures, complemented by digital support offering a library of easily accessible activities. This was viewed as even more important for teachers less interested in physical activity.ConclusionsThe findings from this thesis highlight the importance of shaping healthy movement behaviours already in the preschool age. High-intensity physical activity, sufficient sleep with early bedtimes, and limited screen time were associated with better markers for physical fitness and cardiometabolic health. Preschools offer a unique setting for supporting movement behaviours and providing teachers with practical guidance and resources, while collaborating with parents may strengthen the promotion of healthy movement behaviours in children.List of scientific papersI. Nilsson E, Tigerstrand H, Delisle Nyström C, Löf M. International study of movement behaviours in the early years (SUNRISE): Results from SUNRISE Sweden. [Manuscript]II. Nilsson E, Delisle Nyström C, Migueles JH, Baurén H, Marín-Jiménez N, Henström M, Torres López L, Löf M. Sleep patterns are associated with cardiometabolic risk factors in nine-year-old Swedish children. Acta Paediatr. 2024;113(8):1891-9.https://doi.org/10.1111/apa.17254III. Nilsson E, Migueles JH, Henriksson P, Delisle Nyström C, Löf M. Higher sedentary behaviour and not following screen time guidelines were associated with unfavourable cardiometabolic outcomes in childhood. Acta Paediatr. 2025.https://doi.org/10.1111/apa.70276IV. Nilsson E, Tigerstrand H, Delisle Nyström C, Söderström E, Alexandrou C, Lof M. Promoting healthy lifestyle behaviours in the preschool setting: perceptions and needs of teachers and principals. BMC Public Health. 2025;25:3042.https://doi.org/10.1186/s12889-025-24379-4</p
Improving risk prediction in patients with carotid atherosclerosis : risk scoring, diagnostic imaging and molecular biomarkers
No full textStroke is the third leading cause of death in Sweden, with approximately 20 000 strokes occurring annually. Of these, 10% result in death within the first month. The majority of strokes in Sweden (86%) are ischemic rather than hemorrhagic. Carotid stenosis is estimated to contribute to 8-18% of ischemic strokes. However, this may be underestimated, as emerging evidence suggests that embolic strokes of undetermined source can also originate from non-stenotic carotid plaques.Currently, the decision to perform carotid revascularization in addition to optimized medical therapy is primarily based on the degree of luminal narrowing and the presence of neurological symptoms. Ideally, individuals at risk - those with vulnerable plaque features - would be identified before a stroke occurs. This PhD project aimed to improve the risk prediction in carotid patients by integrating clinical profiles with plaque biological phenotypes, imaging-derived morphological characteristics, and long-term cardiovascular outcomes.Study I was a translational analysis of 101 symptomatic patients with available plaque microarray data. Patients were stratified into high or low stroke risk groups based on CAR and ABCD2 scores. Differential gene expression and gene set enrichment analyses were conducted between high- and low-risk plaques for each risk score. Both CAR and ABCD high-risk plaques exhibited upregulation of genes and biological processes associated with plaque vulnerability, including extracellular matrix degradation, iron ion metabolism, angiogenesis and foam cell differentiation. Notably, the ATP-binding cassette transporter gene ABCB5, previously unassociated with atherosclerosis, was significantly upregulated in high-risk plaques for both scoring systems. Immunohistochemical analysis localized ABCB5 expression to macrophages and neovascularized regions within plaques, suggesting a potential role in intraplaque hemorrhage.Study II, an observational cohort study of 1033 patients, investigated long-term all-cause mortality following carotid endarterectomy and their mortality rate in comparison to an age- and sex matched population. Follow-up data were obtained from national inpatient and death registries. No significant difference in all-cause mortality was observed between asymptomatic and symptomatic patients. However, men exhibited higher mortality, which persisted after adjustments. Increasing age and diabetes were also predictors of mortality. Among women, smoking and cardiac disease were independent risk factors, whereas in men, lipid-lowering and antiplatelet therapies were associated with improved survival, an effect not observed in women. Compared to the matched population, all patient groups experienced excess mortality during the five first years post carotid endarterectomies, with women exhibiting a 2.4-fold higher mortality rate.Study III was a translational study including 238 symptomatic patients with completed ultrasound examination and available RNA sequencing (RNAseq) data. Patients were stratified by stenosis severity into low-grade (Study IV was an observational cohort study of 961 patients undergoing carotid endarterectomy, evaluating long-term risk of major adverse cardiovascular events (MACE) and its components in relation to sex, preoperative symptom status, and predicted risk using CAR and SCORE2/SCORE2-OP models. Follow-up data on stroke and acute coronary syndromes obtained from national registries were validated through manual review of medical records. CEA-treated patients exhibited a persistently high long-term risk of MACE, with similar rates observed in both asymptomatic and symptomatic patients. Men had a higher risk of MACE compared to women, which persisted through the adjustments. Patients classified as high-risk by CAR and SCORE2 had higher crude MACE rates, although these associations were attenuated after adjustments.In summary, carotid plaques from patients with high CAR and ABCD2 scores exhibit biological processes for plaque vulnerability. Low-grade stenosis plaques were similar to high-grade plaques. Although long-term stroke risk after CEA was low, patients remain at high risk for MACEs. A history of stroke is a strong predictor of long-term MACE. Men experience higher rates of all-cause mortality and MACE, while women show excess mortality during the first five years post-CEA.List of scientific papersI. Clinical Risk Scores for Stroke Correlate with Molecular Signatures of Vulnerability in Symptomatic Carotid Patients. Katarina Wadén, Eva Karlöf, Sampath Narayanan, Mariette Lengquist, Göran K. Hansson, Ulf Hedin, Joy Roy, Ljubica Matic. iScience. 2022 Apr 8;25(5):104219. https://doi.org/10.1016/j.isci.2022.104219II. Long Term Mortality Rate in Patients Treated with Carotid Endarterectomy. Katarina Wadén, Rebecka Hultgren, Maria loanna Kotopouli, Peter Gillgren, Joy Roy, Ulf Hedin, Ljubica Matic. Eur J Vasc Endovasc Surg. 2023 Jun;65(6):778-786. https://doi.org/10.1016/j.ejvs.2023.02.079III. Atherosclerotic Plaque Instability in Symptomatic Non-significant Carotid Stenosis. Paul Cyréus, Katarina Wadén, Sofie Hellberg, Otto Bergman, Mariette Lengquist, Eva Karlöf, Andrew Buckler, Ljubica Matic, Joy Roy, David Marlevi, Melody Chemaly, Ulf Hedin. JVS Vasc Sci. 2025 Jan 17:6:100280. https://doi.org/10.1016/j.jvssci.2025.100280IV. Sex-specific Differences in Long-Term Risk of Stroke and Major Adverse Cardiovascular Events after Carotid Endarterectomy. Katarina Wadén, Paul Cyreus, Antti Siika, Joy Roy, Ulf Hedin, Ljubica Matic, Rebecka Hultgren [Manuscript]</p
"Let's chat" : use of mHealth in supporting family caregivers to persons with dementia
No full textBackground: The ageing population and rise of persons with dementia (PWD) have increased the need to support family caregivers (FCs), who experience challenges such as caregiver stress and depression due to daily caregiving demands. Mobile applications (apps) offer innovative solutions for community- based social care professionals to provide support to FCs to PWD living at home. However, limited mobile app-based interventions currently target FCs to PWD living at home. To address this gap, a tailor-made mobile app named STAV (STöd till AnhörigVårdare: Support to family caregivers) was developed.Aim: The overall aim of this doctoral project is to explore experiences and perspectives of FCs to PWD and social care professionals on community-based support in a Swedish context. The doctoral project aims to examine the provision of support through a tailor-made mobile application used as an intervention tool.Methods: Studies I-III were part of an 8-week pilot intervention project in which FCs to PWD received support from healthcare professionals (Study I) and community-based social care professionals (Studies II-III) through the intervention tool STAV. Data for Study I-II were collected post-intervention. Study I used a qualitative explorative design in the feasibility phase, with collected data through semi-structured interviews with FCs of PWD living at home. The data was analysed deductively, guided by qualitative content analysis. Study II used a qualitative descriptive design. Data were collected through semi-structured interviews with social care professionals and FCs to PWD living at home. The data was analysed inductively, guided by thematic analysis.Study III employed an explanatory sequential mixed-methods design, integrating quantitative and qualitative data. Quantitative data were collected pre- and post-intervention through self-administered questionnaires. Qualitative data were collected from the logged chat conversations between the FCs and the social care professionals during the intervention period. Socio-demographic factors were described using descriptive statistics. Paired t-test and a sign test were used to test the statistical significance of mean differences in caregiver stress (primary outcome), and median differences in depressive symptoms (secondary outcome), pre- and post-intervention. FCs were divided into three groups in terms of changes in caregiver stress scores between pre- and post- intervention. Generalized linear models (GLM) were used to determine the association of participation in the intervention on caregiver stress and depressive symptoms controlling for age, gender and relationship to the PWD. Summative content analysis guided the analysis of the logged chat data to identify the type of support provided and received. Changes in caregiver stress were integrated with the chat data to identify patterns in the types of support received.Study IV used a qualitative explorative design, with data collected through semi-structured interviews with social care professionals. The data was analysed using Systematic Text Condensation.Findings: In Study I, 12 FCs, seven women, and five men participated in the interviews. Eleven were spouses, and one was an adult daughter of the PWD they cared for. The findings showed how FCs engaged with the mobile app STAV and other actors in their service network through different levels of value co-creation activities.In Study II, 11 social care professionals and 19 FCs, 16 women and 3 men, participated in the interviews. Most of the FCs were spouses to PWD (n=13), while two were cohabiting partners, three were adult children, and one was a close friend. The FCs had an average age of 72, ranging from 53 to 85 years. The experiences of social care professionals and FCs in providing and receiving support via the mobile app STAV were reflected through three overarching themes: Accessibility to support - Bridging the gap, Engaging from a distance, and Limitations of the support.In study III, a total of 46 FCs to PWD were enrolled in the intervention. However, 11 did not complete post-intervention assessments and were lost to follow-up. Consequently, the final analysis included 35 FCs who completed both pre- and post-intervention evaluations. The FCs had a mean age of 69.4, ranging from 42 to 85 years. Most were women (80%) and partners, either spouses or cohabitating partners (68.6%) and most were living together with the PWD (74.3%). Paired sample t-test showed that the mean score of FCs' caregiver stress was slightly higher post-intervention, 24.1 (9.3), compared to pre- intervention 23.9 (9.2), although this difference was not statistically significant (p=0.87). The median score of FCs' depressive symptoms declined between pre-intervention 6 and post-intervention 5, but this result was also not statistically significant (p=0.57). GLM analyses showed no association between participation in the intervention on caregiver stress after adjusting for age, gender, and relationship to the PWD. However, the mixed-methods analysis indicated subgroup differences, suggesting that frequently provided, tailored support by social care professionals delivered through a mobile app could potentially reduce caregiver stress among FCs to PWD living at home.In Study IV, the social care professionals' (n=13) perspectives on challenges and possibilities in offering support to FCs to community-dwelling PWD of non- European background were reflected through eight themes: (i) Mistrust in the system, (ii) Hard-to-Reach group, (iii) Misalignment of expectations and reality, (iv) Stigmatised situations, (v) Timely contact, (vi) Communicating with the younger generation, (vii) Promoting and adapting support, and (viii) Coordination of services.Conclusions: The intervention tool STAV used in this thesis can serve as a complement to traditional support channels by offering a flexible and essential resource for community-based social care professionals to deliver remote, time-efficient, evidence-based and tailored support to FCs to PWD living at home. Findings suggest that mobile app-based support can lower the threshold for FCs to access support and provide a reassuring presence, even at lower levels of engagement. Additionally, frequent and tailored support may potentially reduce caregiver stress among FCs to PWD living at home.The findings of this thesis may help inform the development and implementation of support services and mHealth interventions aimed at addressing the complex needs of FCs to PWD living at home. However, to ensure broad reach and inclusivity, further adaptations and tailoring are required to address the diverse needs of FCs to PWD, especially to deliver culturally sensitive support for FCs from immigrant backgrounds, who are often identified as hard-to-reach.List of scientific papersI. Kagwa, A.S., Konradsen, H. & Kabir, Z.N. Value co-creation with family caregivers to people with dementia through a tailor-made mHealth application: a qualitative study. BMC Health Serv Res. 22, 1362 (2022). https://doi.org/10.1186/s12913-022-08704-wII. Kagwa, A.S., Dorell, Å., Konradsen, H., Vikström, S. & Kabir, Z.N. Providing and receiving support through a tailor-made mobile app: a qualitative study on experience of professionals and family caregivers to persons with dementia. BMC Geriatr. 24, 554 (2024). https://doi.org/10.1186/s12877-024-05151-6III. Kagwa AS, Longhini J, Islam MN, Vikström S, Dorell Å, Konradsen H, Kabir ZN. Professional Support Through a Tailor-Made Mobile App to Reduce Stress and Depressive Symptoms Among Family Caregivers of People With Dementia: Mixed Methods Pilot Study. JMIR Form Res. 2025;9:e75113. https://doi.org/10.2196/75113IV. Kagwa, A.S., Tiitinen Mekhail, K., Craftman, Å., Konradsen, H., Kabir, Z.N. & Tyrrell, M. Social care professionals' perspectives on challenges and possibilities in offering support to family caregivers to persons with dementia of non-European background: A qualitative study. [Submitted]</p
Assessment and identification of cognitive changes after surgery in older adults
No full textThe overarching aim of this dissertation was to explore methods for assessing postoperative cognitive changes in older adults, including an evaluation of a digital cognitive test battery, and exploring psychological factors influencing cognitive outcomes.Study I was an observational, mixed-methods study with 40 older adult patients (mean age 73, 21 women) who underwent total joint arthroplasty. Postoperative cognitive functions and neuroinflammation were assessed using an analog cognitive test battery, blood biomarkers and qualitative interviews. Five patients met criteria for delayed neurocognitive recovery, however, many patients experienced cognitive issues, especially in executive functions and fatigue. Psychological factors like low mood and sense of control played a role in recovery and daily life, while biomarkers remained normal.Study II was a systematic review and meta-analysis synthesizing psychological factors associated with postoperative delirium, delayed neurocognitive recovery and postoperative neurocognitive disorder in older adults. In total, 27 studies involving 6146 patients were included: depression was slightly linked (OR 1.07 95% CI 0.96-1.18) to postoperative delirium, while anxiety, stress, and certain personality traits were also associated with cognitive outcomes (p Study III was a randomized cross-over study with 50 older adult volunteers (mean age 76, 28 women). Two performance-based measures were compared, an analog cognitive test battery with a self-administered digital one. Participants were interviewed regarding their perceptions of the cognitive assessments. Correlation analyses between the tests were weak to moderate, r=0.19-0.52 and Cohen's d effect sizes were small to large, ranging from 0.25 to 1.43. Qualitative analysis identified two themes: self-competing in a safe environment and experience with technology; participants felt comfortable during the tests, and they reported high usability.Study IV was an observational feasibility study with 24 older adult patients (mean age 77, 13 women) who underwent abdominal surgery, and 5 nurses involved in the recruitment or administration of a digital cognitive test. The feasibility, acceptability and usability of the test was assessed. The test was found feasible, acceptable, and with excellent usability (System Usability Scale mean 87), meeting criteria for a larger trial. Three patients were diagnosed with one-day postoperative delirium, and none were diagnosed with postoperative neurocognitive disorder. The participants considered the test important for assessing cognitive function and easy to use. However, several challenges regarding feasibility were expanded upon in the qualitative interviews including reasons behind low recruitment rates.Conclusions: This dissertation advances understanding of how postoperative cognitive changes can be assessed in older adults. A digital self-administered cognitive test was shown to be feasible and acceptable in healthy older adults and in a small group of highly educated, non-frail patients undergoing abdominal surgery. Depression and postoperative delirium were most consistently studied in the current evidence base. Overall, the findings indicate that postoperative cognitive changes cannot be fully understood by test performance alone; psychological factors and subjective experiences also shape cognitive trajectories after surgery.List of scientific papersThis dissertation is based on the following studies, referred to in text by their Roman numerals. As an author, I retain the copyright to our papers published in these open access journals and have the right to republish them.I. Amirpour, A., Bergman, L., Markovic, G., Liander, K., Nilsson, U., & Eckerblad, J. (2025). Understanding neurocognitive recovery in older adults after total hip arthroplasty-neurocognitive assessment, blood biomarkers and patient experiences: a mixed-methods study. BMJ open, 15(1), e093872. https://doi.org/10.1136/bmjopen-2024-093872II. Amirpour A, Bergman L, Markovic G, Eckerblad J, Nilsson, U, Falk, A. Psychological factors associated with postoperative cognitive outcomes - a systematic review and meta-analysis. [Submitted] III. Amirpour, A., Eckerblad, J., Bergman, L., & Nilsson, U. (2024). Comparing analog and digital neurocognitive tests with older adults: a study of the ISPOCD battery vs. a digital test battery from Mindmore. BMC geriatrics, 24(1), 34. https://doi.org/10.1186/s12877-023-04648-wIV. Amirpour A, Saarijärvi M, Eckerblad J, Markovic G, Thorell A, Nilsson U, Bergman L. Evaluation of a digital, self-administered, cognitive test battery in older adult patients undergoing abdominal surgery: a non-randomized feasibility trial. [Submitted]</p